This invention relates to acetylenic hydroxamic acids which act as inhibitors of TNF-xcex1 converting enzyme (TACE). The compounds of the present invention are useful in disease conditions mediated by TNF-xcex1, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn""s disease and degenerative cartilage loss.
Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors. It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren""s syndrome, myopia, ocular tumors, ocular angiogenesis/neo-vascularization and corneal graft rejection. For recent reviews, see: (1) Recent Advances in Matrix Metalloproteinase Inhibitor Research, R. P. Beckett, A. H. Davidson, A. H. Drummond, P. Huxley and M. Whittaker, Research Focus, Vol. 1, 16-26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4(1): 7-16, (3) Curr. Medicinal Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther. Patents (1995) 5(2): 1087-110, (5) Exp. Opin. Ther. Patents (1995) 5(12): 1287-1196: (6) Exp. Opin. Ther. Patents (1998) 8(3): 281-259.
TNF-xcex1 converting enzyme (TACE) catalyzes the formation of TNF-xcex1 from membrane bound TNF-xcex1 precursor protein. TNF-xcex1 is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis [Shire, M. G.; Muller, G. W. Exp. Opin. Ther. Patents 1998, 8(5), 531; Grossman, J. M.; Brahn, E. J. Women""s Health 1997, 6(6), 627; Isomaki, P.; Punnonen, J. Ann. Med. 1997, 29, 499; Camussi, G.; Lupia, E. Drugs, 1998, 55(5), 613.] septic shock [Mathison, et. al. J. Clin. Invest. 1988, 81, 1925; Miethke, et. al. J. Exp. Med. 1992, 175, 91.], graft rejection [Piguet, P. F.; Grau, G. E.; et. al. J. Exp. Med. 1987, 166, 1280.], cachexia [Beutler, B.; Cerami, A. Ann. Rev. Biochem. 1988, 57, 505.], anorexia, inflammation [Ksontini, R,; MacKay, S. L. D.; Moldawer, L. L. Arch. Surg. 1998, 133, 558.], congestive heart failure [Packer, M. Circulation, 1995, 92(6), 1379; Ferrari, R.; Bachetti, T.; et. al. Circulation, 1995, 92(6), 1479.], post-ischaemic reperfusion injury, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance [Hotamisligil, G. S.; Shargill, N. S.; Spiegelman, B. M.; et. al. Science, 1993, 259, 87.] and HIV infection [Peterson, P. K.; Gekker, G.; et. al. J. Clin. Invest. 1992, 89, 574; Pallares-Trujillo, J.; Lopez-Soriano, F. J. Argiles, J. M. Med. Res. Reviews, 1995, 15(6), 533.]], in addition to its well-documented antitumor properties [Old, L. Science, 1985, 230, 630.]. For example, research with anti-TNF-xcex1 antibodies and transgenic animals has demonstrated that blocking the formation of TNF-xcex1 inhibits the progression of arthritis [Rankin, E. C.; Choy, E. H.; Kassimos, D.; Kingsley, G. H.; Sopwith, A. M.; Isenberg, D. A.; Panayi, G. S. Br. J. Rheumatol. 1995, 34, 334; Pharmaprojects, 1996, Therapeutic Updates 17 (October), 197-M2Z.]. This observation has recently been extended to humans as well as described in xe2x80x9cTNF-xcex1 in Human Diseasesxe2x80x9d, Current Pharmaceutical Design, 1996, 2, 662.
It is expected that small molecule inhibitors of TACE would have the potential for treating a variety of disease states. Although a variety of TACE inhibitors are known, many of these molecules are peptidic and peptide-like which suffer from bioavailability and pharmacokinetic problems. In addition, many of these molecules are non-selective, being potent inhibitors of matrix metalloproteinases and, in particular, MMP-1. Inhibition of MMP-1 (collagenase 1) has been postulated to cause joint pain in clinical trials of MMP inhibitors [Scrip, 1998, 2349, 20] Long acting, selective, orally bioavailable non-peptide inhibitors of TACE would thus be highly desirable for the treatment of the disease states discussed above.
Sulfone hydroxamic acid inhibitors of MMPs, of general structure I have been disclosed [Burgess, L. E.; Rizzi, J. P.; Rawson, D. J. Eur Patent Appl. 818442. Groneberg, R. D.; Neuenschwander, K. W.; Djuric, S. W.; McGeehan, G. M.; Burns, C. J.; Condon, S. M.; Morrissette, M. M.; Salvino, J. M.; Scotese, A. C.; Ullrich, J. W. PCT Int. Appl. WO 97/24117. Bender, S. L.; Broka, C. A.; Campbell, J. A.; Castelhano, A. L.; Fisher, L. E.; Hendricks, R. T.; Sarma, K. Eur. Patent Appl. 780386. Venkatesan, A. M.; Grosu, G. T.; Davis, J. M.; Hu, B.; O""Dell, M. J. PCT Int. Appl. WO 98/38163.]. An exemplification of this class of MMP inhibitor is RS-130830, shown below. 
Within the sulfone-hydroxamic acid class of MMP inhibitor, the linker between the sulfone and hydroxamic acid moieties has been extended to three carbons (I, n=2) without significant loss in potency [Barta, T. E.; Becker, D. P.; Villamil, C. I.; Freskos, J. N.; Mischke, B. V.; Mullins, P. B.; Heintz, R. M.; Getman, D. P.; McDonald, J. J. PCT Int. Appl. WO 98/39316. McDonald, J. J.; Barta, T. E.; Becker, D. P.; Bedell, L. J.; Rao, S. N.; Freskos, J. N.; Mischke, B. V. PCT Int. Appl. WO 98/38859.].
Piperidine sulfone hydroxamic acids, II (n=1) have been reported [Becker, D. P.; Villamil, C. I.; Boehm, T. L.; Getman, D. P.; McDonald, J. J.; DeCrescenzo, G. A. PCT Int. Appl. WO 98/39315.]. Similar piperidine derivatives in which the methylene linking the piperidine ring to the sulfone has been deleted (II, n=0) have been reported [Venkatesan, A. M.; Grosu, G. T.; Davis, J. M.; Baker, J. L. PCT Int. Appl. WO 98/37877.]. 
Sulfone-hydroxamic acids III, in which a hydroxyl group has been placed alpha to the hydroxamic acid, have been disclosed [Freskos, J. N.; Boehm, T. L.; Mischke, B. V.; Heintz, R. M.; McDonald, J. J.; DeCrescenzo, G. A.; Howard, S. C. PCT Int. Appl. WO 98/39326. Robinson, R. P. PCT Int. Appl. WO 98/34915.]. 
Sulfone-based MMP inhibitors of general structure IV, which utilize a thiol as the zinc chelator, have been reported [Freskos, J. N.; Abbas, Z. S.; DeCrescenzo, G. A.; Getman, D. P.; Heintz, R. M.; Mischke, B. V.; McDonald, J. J. PCT Int. Appl. WO 98/03164]. 
Inhibitors of stromelysin with general structure V have been disclosed [Shuker, S. B.; Hajduk, P. J.; Meadows, R. P.; Fesik, S. W. Science, 1996, 274, 1531-1534. Hajduk, P. J.; Sheppard, G.; Nettesheim, D. G.; Olejniczak, E. T.; Shuker, S. B.; Meadows, R. P.; Steinman, D. H.; Carrera, Jr., G. M.; Marcotte, P. A.; Severin, J.; Walter, K.; Smith, H.; Gubbins, E.; Simmer, R.; Holzman, T. F.; Morgan, D. W.; Davidsen, S. K.; Summers, J. B.; Fesik, S. W. J. Am. Chem. Soc. 1997, 119, 5818-5827. Olejniczak, E. T.; Hajduk, P. J.; Marcotte, P. A.; Nettesheim, D. G.; Meadows, R. P.; Edalji, R.; Holzman, T. F.; Fesik, S. W. J. Am. Chem. Soc. 1997, 119, 5828-5832. Fesik, S. W.; Summers, J. B.; Davidsen, S. K.; Sheppard, G. S.; Steinman, D. H.; Carrera, G. M.; Florjancic, A.; Holms, J. H. PCT Int. Appl. WO 97/18188.]. 
Salah et al., Liebigs Ann. Chem. 195, (1973) discloses some aryl substituted thio and aryl substituted sulfonyl acetohydroxamic acid derivatives of general formula 1. These compounds were prepared to study the Mannich reaction. Subsequently, they were tested for their fungicidal activity. 
Some sulfone carboxylic acids are disclosed in U.S. Pat. No. 4,933,367. Those compounds were shown to exhibit hypoglycemic activity.
The present invention relates to novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-xcex1 converting enzyme (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection.
In accordance with this invention there is provided a group of compounds of general formula I: 
wherein:
R1 is hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or xe2x80x94C4-C8-cycloheteroalkyl;
R2 and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, xe2x80x94CN, or xe2x80x94CCH;
R7 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, xe2x80x94C(O)xe2x80x94R1, xe2x80x94SO2xe2x80x94R1, xe2x80x94C(O)xe2x80x94NHR1, xe2x80x94C(O)NR5R6, xe2x80x94C(O)R1NR5R6, xe2x80x94C(O)xe2x80x94OR1, xe2x80x94C(NH)xe2x80x94NH.2.
R8, R9, R10, and R11 are each, independently, hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, xe2x80x94C4-C8-cycloheteroalkyl, alkyl of 1-18 carbon atoms, alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon atoms; with the proviso that one of the pairs R8 and R9, R9 and R10 or R10 and R11, together with the carbon atom or atoms to which they are attached, form a cycloalkyl ring of 3-6 carbon atoms, or a xe2x80x94C4-C8-cycloheteroalkyl ring;
R12 is hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, xe2x80x94C4-C8-cycloheteroalkyl, or alkyl of 1-6 carbon atoms;
A is O, S, SO, SO2, NR7, or CH2;
X is O, S, SO, SO2, NR7, or CH2;
Y is aryl or heteroaryl, with the proviso that A and X are not bonded to adjacent atoms of Y; and
n is 0-2; or a pharmaceutically acceptable salt thereof.
In some preferred aspects of the invention, Y is phenyl, pyridyl, thienyl, furanyl, imidazolyl, triazolyl or thiadiazolyl, with the proviso that A and X are not bonded to adjacent atoms of Y.
In still other preferred embodiments of the invention Y is phenyl, thienyl or furanyl.
In accordance with certain preferred embodiments of the invention R8 and R9, together with the carbon atom to which they are attached form a C4-C8 cycloheteroalkyl ring and K is NR7.
The most preferred matrix metalloproteinase and TACE inhibiting compounds of this invention are:
1-(4-Bromo-benzyl)-4-(4-but-2-ynyxoy-benzenesulfonyl)-piperdine-4-carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine-4-carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-chloro-benzyl)-piperdine-4-carboxylic acid hydroxyamide;
1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid hydroxamide;
1-(4-Bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid hydroxyamide;
1-(4-Bromo-benzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzyl)-piperdine-4-carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic acid hydroxamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidine-4-carboxylic acid hydroxamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4-carboxylic acid hydroxamide;
1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid hydroxyamide;
1-(4-Bromo-benzyl)-4-[4-(4-piperdin-4-yl-but-2-ynyloxy)-benzenesulfonyl]-piperdine-4-carboxylic acid hydroxyamide;
1-(4-Bromo-benzyl)-4-[4-(4-morpholin-4-yl-but-2-ynyloxy)-benzene-sulfonyl]-piperdine-4-carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-phenylsulfanyl)-4-hydroxycarbamoyl-piperidine-1-carboxylic acid tert-butyl ester;
4-(4-But-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid hydroxyamide
1-(4-Bromo-benzyl)-4-(4-but-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-benzenesulfonylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-benzenesulfinylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide;
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxytetrahydro-2H-pyran-4-carboxamide;
1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperdine carboxamide;
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-isopropyl-4-piperidine carboxamide;
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-(3-pyridinylmethyl)-4-piperidine carboxamide;
3-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-ethyl-N-hydroxy-3-piperidine-carboxarnide;
3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-N-hydroxy-3-piperidinecarboxamide;
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-[4-(2-piperidin-1yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide;
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-(3-pentanyl)-piperidine-4-carboxylic acid hydroxyamide;
1-(4-Methoxy-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide;
1-(4-Chloro-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide;
tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl}methyl)-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate;
4-({[4-(But-2-ynyloxy)phenyl]thio}methyl)-N-hydroxypiperidine-4-carboxamide;
tert-Butyl-4-({[4-(2-butynyloxy)phenyl]sulfinyl}methyl)-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate;
4-[[[4-(2-Butynyloxy)phenyl]sulfinyl]methyl]-N-hydroxy-4-piperidine-carboxamide;
tert-Butyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino)-carbonyl]piperidine-1-carboxylate;
tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxyla;
1-Acetyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]-N-hydroxy-4-piperidinecarboxamide;
1-(2-Butynyl)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide hydrochloride;
N-1-(tert-Butyl)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-1,4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-1,4-l]sulfonyl}-methyl)-Nxcx9c4xcx9c-hydroxy-1,4-piperidinedicarboxamide;
Methyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate;
Benzyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino)-carbonyl]-1-piperidinecarboxylate;
1-Benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide;
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide;
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoyl]-4-piperidinecarboxamide;
1-[Amino(imino)methyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-1]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-oxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide;
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(4-hydroxy-2-butynyl)-henyl]sulfonyl}methyl)-N-hydroxy-1-(4-hydroxy-2-butynyl)-4-piperidinecarboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-1-ethyl-N-hydroxypiperidine-4-carboxamide triflouroacetic acid salt;
2-chloro-5-(chloromethyl) thiophene4-({[4-(But-2-ynyloxy)phenyl]-sulfonyl}-methyl)-1-[(5-chlorothien-2-yl)methyl]-N-hydroxypiperidine-4-carboxamide triflouroacetic acid salt;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(pyridin-4-ylmethyl)piperidine-4-carboxamide triflouroacetic acid salt;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(pyridin-3ylcarbonyl)piperidine-4-carboxamide triflouroacetic acid salt;
1-Benzoyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-piperidine-4-carboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(thien-2-ylcarbonyl) piperidine-4-carboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-1-ethyl-N-4-hydroxy-piperidine-1,4-dicarboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-N-1-phenyl-piperidine-1,4-dicarboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-1-,N-1-diethyl-N-4-hydroxypiperidine-1,4-dicarboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(morpholin-4-ylcarbonyl)piperidine-4-carboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-N-1-methyl-N-1-phenylpiperidine-1,4-dicarboxamide;
Octyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino)-carbonyl]piperidine-1-carboxylate;
4-Methoxyphenyl4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino)carbonyl]piperidine-1-carboxylate;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(phenylsulfonyl)piperidine-4-carboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidine-4-carboxamide;
1-[2-(Benzylamino)acetyl]-4-({[4-(but-2-ynyloxy)phenyl]-sulfonyl}methyl)-N-hydroxypiperidine-4-carboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(2-morpholin-4-ylacetyl)piperidine-4-carboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[2-(4-methyl-piperazin-1-yl)acetyl]piperidine-4-carboxamide;
1-Acetyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid hydroxamide;
1-Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid hydroxamide;
1-(4-Methoxybenzoyl)-4-(4-but-2-ynyloxy benzenesulfonyl)piperidine-4-carboxylic acid hydroxamide;
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(pyrrolidine-1-carbonyl)-4-piperidinecarboxamide;
Ethyl 4-(4-but-2-ynyloxybenzenesulfonyl)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate;
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(trifluoromethyl)sulfonyl]-4-piperidinecarboxamide;
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(3-pyridinylcarbonyl)-4-piperidinecarboxamide;
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(2-thienylcarbonyl)-4-piperidinecarboxamide;
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(4-methoxyphenyl)-sulfonyl]-4-piperidinecarboxamide;
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide;
Tert-butyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxalate;
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperidinecarboxamide hydrochloride;
Methyl ({4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl]-1-piperidinyl}methyl)benzoate hydrochloride;
4-({4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl]-1-piperidinyl}methyl)benzoic acid hydrochloride;
1-[4-(Aminocarbonyl)benzyl]-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperidinecarboxamide hydrochloride;
Tert-butyl 4-{[4-(but-2-ynyloxy)phenyl]sulfinyl}-4-[(hydroxyamino)-carbonyl]piperidine-1-carboxalate;
4-(4-(But-2-ynyloxy-benzenesulfinyl)-piperidine-4-carboxylic acid hydroxamide hydrochloride; and
1-(4-Bromo-benzyl)-4-(4-But-2-ynyloxy-benzenesulfinyl)-piperidine-4-carboxylic acid hydroxamide hydrochloride;
and pharmaceutical salts thereof.
Heteroaryl, as used throughout, is a 5-10 membered mono- or bicyclic aromatic ring having from 1-3 heteroatoms selected from N, NR7, S and O. Heteroaryl is preferably 
wherein K is defined as O, S or xe2x80x94NR7, and R7 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, xe2x80x94C(O)xe2x80x94R1, xe2x80x94SO2xe2x80x94R1, xe2x80x94C(O)xe2x80x94NHR1, xe2x80x94C(O)NR5R6, xe2x80x94C(O)R1, NR5R6, xe2x80x94C(O)xe2x80x94OR1, xe2x80x94C(NH)xe2x80x94NH2.
Preferred heteroaryl rings include pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole, indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole, and benzoxazole. Heteroaryl groups of the present invention may be mono or disubstituted.
xe2x80x94C4-C8-cycloheteroalkyl is defined as 
wherein K is O, S or NR7 and R7 is as defined before. Preferred heterocycloalkyl rings include piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran or pyrrolidine. Heterocycloalkyl groups of the present invention may optionally be mono- or di-substituted.
Aryl, as used herein refers to phenyl or naphthyl aromatic rings which may, optionally be mono- or di-substituted.
Alkyl, alkenyl, alkynyl, and perfluoroalkyl include both straight chain as well as branched moieties. Alkyl, alkenyl, alkynyl, and cycloalkyl groups may be unsubstituted (carbons bonded to hydrogen, or other carbons in the chain or ring) or may be mono- or poly-substituted.
Aralkyl as used herein refers to a substituted alkyl group, -alkyl-aryl, wherein alkyl is lower alkyl and preferably from 1-3 carbon atoms, and aryl is as previously defined.
Heteroaralkyl as used herein refers to a substituted alkyl group, alkyl-heteroaryl wherein alkyl is lower alkyl and preferably from 1-3 carbon atoms, and heteroaryl is as previously defined.
Halogen means bromine, chlorine, fluorine, and iodine.
Suitable substituents of aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, alkenyl, alkynyl and cycloalkyl include, but are not limited to halogen, alkyl of 1-6 carbon atoms; alkenyl of 2-6 carbon atoms; alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, xe2x80x94OR5, xe2x95x90O, xe2x80x94CN, xe2x80x94COR5, perfluoroalkyl of 1-4 carbon atoms, xe2x80x94O-perfluoroalkyl of 1-4 carbon atoms, xe2x80x94CONR5R6, xe2x80x94S(O)nR5, xe2x80x94OPO(OR5)OR6, xe2x80x94PO(OR5)R6, xe2x80x94OC(O)OR5, xe2x80x94OR5NR5R6, xe2x80x94OC(O)NR5R6, xe2x80x94C(O)NR5OR6, xe2x80x94COOR5, xe2x80x94SO3H, xe2x80x94NR5R6, xe2x80x94N[(CH2)2]2NR5, xe2x80x94NR5COR6, xe2x80x94NR5COOR6, xe2x80x94SO2NR5R6, xe2x80x94NO2, xe2x80x94N(R5)SO2R6, xe2x80x94NR5CONR5R6, xe2x80x94NR5C(xe2x95x90NR6)NR5R6, xe2x80x94NR5C(xe2x95x90NR6)N(SO2R5)R6, xe2x80x94NR5C(xe2x95x90NR6)N(Cxe2x95x90OR5)R6, -tetrazol-5-yl, xe2x80x94SO2NHCN, xe2x80x94SO2NHCONR5R6, phenyl, heteroaryl or xe2x80x94C4-C8-cycloheteroalkyl;
wherein
xe2x80x94NR5R6 may form a pyrrolidine, piperidine, morpholine, thiomorpholine, oxazolidine, thiazolidine, pyrazolidine, piperazine, or azetidine ring;
R5and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or xe2x80x94C4-C8-cycloheteroalkyl;
R7 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, xe2x80x94C(O)xe2x80x94R1, xe2x80x94SO2xe2x80x94R1, xe2x80x94C(O)xe2x80x94NHR1, xe2x80x94C(O)xe2x80x94OR1, xe2x80x94C(NH)xe2x80x94NH2; and n is 0-2.
When a moiety contains more than substituent with the same designation each of those substituents may be the same or different.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, when a compound of this invention contains an acidic moiety.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. It is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
The compounds of this invention are shown to inhibit the enzymes MMP-1, MMP-9, MMP-13 and TNF-xcex1 converting enzyme (TACE) and are therefore useful in the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, graft rejection, insulin resistance, bone disease and HIV infection. In particular, the compounds of the invention provide enhanced levels of inhibition of the activity of TACE in vitro and in cellular assay and/or enhanced selectivity over MMP-1 and are thus particularly useful in the treatment of diseases mediated by TNF.
Also according to the present invention, there are provided processes for producing the compounds of the present invention.
The compounds of the present invention may be prepared according to one of the general processes outlined below.
The compounds of the present invention, where n=0, X=O, S or NR7, and R8 and R9 taken with the carbon atom to which they are attached, form a six membered heterocyclic ring containing Nxe2x80x94R7, S or O and A=S, SO or SO2 may be prepared according to one of the general processes outlined below.
As outlined in scheme 1, the appropriately substituted mercaptan derivative was alkylated using xcex1-bromo acetic acid ester derivative in refluxing chloroform using N,N-diisopropylethylamine as base. The sulfide derivative thus obtained was reacted with appropriately substituted propargyl bromide derivative in refluxing acetone using K2CO3 as base. In the case of X=xe2x80x94Nxe2x80x94R7 the N-alkylation can be carried out in DMF/NaH at room temperature. The sulfide derivative thus obtained was oxidized using m-chloroperbenzoic acid in CH2Cl2 or by using Oxone in methanol/water. The sulfone thus obtained can be converted to the corresponding piperidine derivative by reacting it with bis(2-chloroethyl)N-substituted amine derivative. 
a. Diisopropylethyamine/CHCl3/RT/3 Hr; b. K2CO3/Acetone/Prpargyl bromide derivative; c. Oxone/MeOH:THF/THF/RT; d: K2CO3/18-Crown-6/(C4H9)4NBr/Acetone/Bis-2-chloroethyl N-substituted amine derivative/Reflux; e: NaOH/THF:MeOH/RT and (COCl)2/NH2OH.HCl/Et3N/THF/DMF.
Bis-2-chloroethyl N-substituted amines can be prepared from the substituted diethanolamine and thionyl chloride. (Scheme 2). The cyclic product obtained by the above mentioned operation, can be hydrolyzed to carboxylic acid and subsequently converted to the hydroxamic acid as outlined in scheme 1. 
a: Diisopropylethylamine/R7Br/CHCl3/Reflux; b: SOC2/CH2Cl2/Reflux
The corresponding sulfides and sulfoxides can be prepared starting from the corresponding saturated heterocyclic carboxylic acid derivative. (Scheme-3). N-Boc protected isonipecotic acid can be lithiated using tert-butyllithium and the resulting anion was reacted with appropriately substituted disufides. The sufide derivative can be converted to hydroxamic acids by the procedure outlined above. 
a: tert-Butyllithium/xe2x88x9278xc2x0 C./THF/Bis(4-but-2-ynyloxyphenyl)disufide; b: (COCl)2/NH2OH.HCl/Et3N/DMF/CH2Cl2; c: 1.HCl/Dioxane; c: 2:R7Br/Et3N; d: MeOH/30% H2O2 
These sulfides subsequently can be converted to the sulfoxides using 30% hydrogen peroxide at room temperature. The required disulfides can be prepared from the appropriately substituted thiol and DMSO/HCl oxidation. This procedure can be applied to any saturated, fused or non-fused heterocyclic carboxylic acid derivative. (Scheme 4) 
a: tert-Butyllithium/xe2x88x9278xc2x0 C./THF/Bis(4-but-2-ynyloxyphenyl)disufide; b: (COCl)2/NH2OH.HCl/Et3N/DMF/CH2Cl2; c: CH2Cl2/HCl/MeOH/R7Br/Et3N; d: MeOH/30% H2O2; e: Oxone/MeOH/THF/Rt.
Alternatively, sulfone derivatives can also be lithiated and carbonylated using either dry ice or CO2 gas. (Scheme 5). The sulfone derivative can be a mono heterocyclic, bicyclic, benzo fused or hetero aryl such as pyridyl, thienyl, furanyl, pyrazinyl, pyrimidyl, thiazolyl fused ring systems. 
a: n-Butyllithium and quench with CO2; b: (COCl)2/DMF/NH2OH.HCl/Et3N
The oxygen analogue can be prepared (Scheme 6) from the appropriately substituted alkynyloxy-benzenesulfonyl acetic acid ethyl ester and 2-chloroethyl ether. The corresponding pyran derivative can be hydrolyzed to carboxylic acid, which can be converted to the hydroxamic acid derivative. 
a: 2-Chloroethyl ether/K2CO3/18-Crown-6/n-(C4H9)4 Br/Acetone/Reflux;
b: 10N. NaOH/THF/MeOH/RT;
c: (COCl)2/DMF/NH2OH.HCl/Et3N.
The thiols used as intermediates for the synthesis of compounds of the invention can be made according to Scheme 7. Thus, sulfonic acid salts 1, where XR50 is a hydroxy, thiol or substituted amino moiety may be alkylated with acetylenes 2, where J is a suitable leaving group such as halogen mesylate, tosylate, or triflate to give 3. Acetylenes 2 are commercially available or known compounds, or they may be synthesized by known methods by those skilled in the art. The sulfonic acid salts 3 may be converted into the corresponding sulfonyl chloride or other sulfonylating agent 4 by known methods, such as reaction with oxalyl chloride, phosphorus oxychloride or other reagent compatible with substituents R1, R2, and R3 and the acetylene. The sulfonyl chloride 4 can then be reduced to the corresponding thiol 5 using triphenylphosphine in a suitable solvent mixture such as dichloromethane/DMF at a temperature of between xe2x88x9220xc2x0 C. and 30xc2x0 C. 
Alternatively, disulfide 6 may be converted into di-acetylene 7 by reaction with compounds 2, followed by reduction of the disulfide bond to provide the desired thiols 5. Bisacetylenes 7 may also be converted into thiols 5 via sulfonyl chlorides 4. Alkylation of the phenol, thiophenol, aniline or protected aniline 8 with 2 to give 9, followed by reaction with chlorosulfonic acid provides sulfonic acids 10 which are readily converted into 4 with oxalyl chloride or similar reagents and subsequently reduced to thiols 5. Thiophenols 11 are also precursors to 5 via protection of the thiol 5 with a triphenylmethyl or other suitable protecting group, alkylation of XH, where X is O, N or S, and deprotection of the sulfur. 
Compounds of the invention wherein X is N, O, S, SO or SO2, can be synthesized according to Scheme 8 and Scheme 9. Alkylation of the para-disubstituted aryl 14, or its protected equivalent, with acetylene 2 in the presence of a base such as potassium carbonate in a polar aprotic solvent such as acetone or DMF at a temperature of between 20xc2x0 C. and 120xc2x0 C. provides the mono-propargylic ether 15. Those skilled in the art will recognize that protecting groups may be required to avoid undesirable side reactions and increase the yield of the reaction. The need and choice of protecting group for a particular reaction is known to those skilled in the art. Reaction of this compound with .-propiolactone, or a substituted propiolactone derivative (wherein the substituents are defined as before), in the presence of a base such as potassium t-butoxide in a polar solvent, or solvent mixture, such as THF or DMF affords the carboxylic acid 16. Conversion of carboxylic acid 16 into the corresponding hydroxamic acid, 17, is accomplished via formation of an activated ester derivative such as an acid chloride or acid anhydride followed by reaction with hydroxylamine. It is understood by those skilled in the art that when A is sulfur, in Scheme 8 and all relevant subsequent Schemes, the sulfur can be oxidized to the corresponding sulfoxide or sulfone at any stage after formation of the thioether, using a suitable oxidant such as oxone, air, m-chloroperbenzoic acid or hydrogen peroxide.
Compounds 18 are also accessible from the Michael addition of compound 15 to a cyclic acrylate ester, or substituted acrylate ester (substituents are defined as before), to provide 18, in which R30 is hydrogen or a suitable carboxylic acid protecting group. Deprotection of the ester moiety then provides carboxylic acid, which can be converted into the analogous hydroxamic acid. Similarly, Michael addition of mono-protected 1,4-disubstituted aryl 19, where XR25 is hydroxy or protected hydroxy, thiol or amine, gives compound 20. Unmasking of the protecting group gives thiol, aniline or phenol 21 which can be alkylated with propargyl derivative 2 to provide 18. Mono protected compound 19 can also be reacted with xcex2-propionolactone to provide 22. Alternatively, 22 can be deprotected followed by alkylation to give 16 and 17.
Synthesis of compounds of the invention wherein X is N, O, S, SO or SO2, and the linker between the proximal heteroatom and the hydroxamic acid is a one or three carbon chain can be synthesized according to Scheme 9. Compound 19, where XR25 is hydroxy or protected hydroxy, thiol or amine, can react with ester 24 or lactone 24a, in which R30 is hydrogen or a suitable carboxylic acid protecting group, with an appropriately substituted leaving group such as halogen, tosylate, mesylate or triflate, to provide 25. Unmasking of the heteroatom X of compound 25 then provides 26, which may next be alkylated with propargylic derivative 2 to give acetylene-ester 27. Ester 27 can be converted into the corresponding hydroxamic acid 28 through conversion of the ester into the carboxylic acid by acid or base hydrolysis, followed by conversion into the hydroxamic acid as described in Scheme 1. Alternatively, compound 15, prepared as shown in Scheme 8, can be alkylated directly with ester 24 or lactone 24a to give 27 and then 28. Substituents on the carbon alpha to the hydroxamic are defined as before. 
Compounds of the invention wherein A is a methylene or substituted methylene group, and X is oxygen, can be obtained according to Scheme 10. Esters or carboxylic acids 29, commercially available or known in the literature, can be converted into the corresponding phenols, 30. Alkylation of the phenol with acetylene 2 gives the propargylic ethers, 31, which can be converted into the corresponding carboxylic acids and thence the hydroxamic acids, 33, as described in Scheme 1. Substituents on the carbon alpha to the hydroxamic, are defined as before. 
Compounds of the invention wherein A is xe2x80x94SO2xe2x80x94, and R8 and R9 are not hydrogen, are available starting from 4-fluorobenzenethiol 34 as shown in Scheme 11. Deprotonation of the thiol followed by reaction with .-propiolactone, or an acrylate ester, or ester deriavtive 24, and subsequent oxidation of the resulting thioether provides sulfone-acid 35. Displacement of the 4-fluoro substituent of 35, or its corresponding ester, with propargyl derivative 36, wherein X is N, O or S, then provides sulfone 16. Compound 16 can be converted into the compounds of the 15 invention according to Scheme 1. Fluoroaryl 35 can also react with a masked hydroxyl, thiol or amino group (HXR40, wherein R40 is a suitable protecting group) in the presence of a base such as sodium hydride in a polar aprotic solvent such as DMF to provide 36. Deprotection of 36 followed by alkylation with acetylenic derivative 2 then gives 16. 
Compounds of the invention wherein X is NH are also available starting from the appropriate commercially available nitro aryl compound 38 (Scheme 12).Thus, the anion of compound 38 can be used to alkylate xcex2-propiolactone, or a substituted derivative, or a cyclic acrylate ester to provide 40 and 39 respectively. Reduction of the nitro group followed by alkylation of the resulting aniline then gives 16. Compound 38 can also be alkylated with ester derivative 24 to afford nitro-ester 40, followed by reduction to give the corresponding aniline, analogous to compound 26 of Scheme 9. 
Compounds of the invention wherein R11, alpha to the hydroxamic acid, is a hydroxy group can be obtained via epoxides 41, as shown in Scheme 13. These epoxides are available through the oxidation of the corresponding acrylate esters or by the Darzens reaction of an alpha-halo ester with a ketone. Reaction of the epoxide with thiol, phenol or aniline 19 in the presence of base or Lewis acid catalyzed epoxide ring opening, provides alpha-hydroxy ester 42. Deprotection of 42 followed by alkylation with propargyl derivative 2 gives 44. Conversion of the ester of 44 into the analogous hydroxamic acid as described in Scheme 1 then provides 45. Compounds 45, wherein A is sulfur, may be converted into the analogous sulfoxides or sulfones through oxidation with hydrogen peroxide, air, Oxone or other suitable reagent at this point. Similarly, thiol, phenol or aniline 15 can be reacted with 41 to give 44. The hydroxyl group of compound 43 can also be manipulated through its conversion into a suitable leaving group, such as halide or sulfonate ester, followed by displacement with various nucleophiles including amines to provide 44. 
Another route to alpha-hydroxy hydroxamic acids of the invention is shown in Scheme 14. Compound 15 can be alkylated with alcohol 46 to give 47. Oxidation of the alcohol, with or without concomitant oxidation of the thioether (for A=S), gives the aldehyde 48. Reaction of aldehyde 48 with trimethylsilyl cyanide or other suitable reagent then provides the cyanohydrin 49. Hydrolysis of the nitrile 49 into the corresponding carboxylic acid followed by conversion into the hydroxamic acid as described in Scheme 1 gives 50. 
Compounds described in the present invention (from Example 30 to 63) were prepared as per the Schemes 15 and Scheme 16. In scheme 15, the t-Boc-protected ethyl isonipecotate 51 was carefully alkylated using diiodomethane to yield the monoiodo compound 52. This was subsequently converted to different hydroxamic acid derivatives as depicted in Scheme 15. In scheme 16, the N-Boc group was selectively removed using TMSOTf/2,6-Lutidine. After the derivatisation of the nitrogen, the O-tBu was removed using TFA in methylene chloride. 
Alternatively, compounds (wherein A=SO2 and n=0) described in examples 64 to 74 and 80 were prepared as depicted in Scheme 17. 
Experimental